This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Mixed Lineage Leukemia (MLL) protein catalyzes histone H3 lysine 4 (H3K4) methylation, which is an epigenetic mark essential for the regulation of HOX genes in hematopoiesis and development. Translocations that disrupt the MLL gene are present in a unique group of acute leukemias, often predicting a poor prognosis. Other MLL rearrangements and amplifications increase MLL's enzymatic activity and are oncogenic. MLL contains an evolutionarily conserved ~130 amino acid SET domain that catalyzes H3K4 methylation. Recent studies indicate that the enzymatic activity of MLL is regulated by a conserved complex of proteins including WDR5, RbBP5, and ASH2L. These proteins form an independent complex that binds to MLL and regulates MLL's ability to mono-, di-, or trimethylate H3K4, a phenomenon known as 'Product Specificity'. Since different levels of methylation of H3K4 are associated with different transcriptional outcomes, it is imperative to understand the molecular mechanisms by which the product specificity of MLL is regulated. Despite the important biological role of MLL and its involvement in human leukemia, there is currently little information about the protein-structural features that are responsible for the enzymatic activity of MLL. The long-term goal of this research is to fully characterize the histone methyltransferase activity of MLL to facilitate the identification and rational design of new anti-cancer drugs for the treatment of human leukemias. This proposal takes a structure-function approach to investigate the molecular mechanisms of MLL SET domain regulation by protein-protein interactions. We have mapped the site of interaction between MLL and WDR5, and have obtained crystals of WDR5 with a peptide derived from MLL. The initial structure diffracted to 1.72 angstroms, and elucidtaed the peptide binding site. For this investigation, we would like to obtain higher resolution data with a longer peptide to determine if other interactions between MLL and WDR5 are important.